Smokeless Tobacco Lesions

The term smokeless tobacco, also known as dip, plug, chew, or spit tobacco, refers to both chewing tobacco (coarse cut) and snuff (fine cut). Three types of smokeless tobacco are commonly manufactured: loose-leaf chewing tobacco, moist snuff, and dry snuff.[4] Dry snuff, which is inhaled nasally, or in the more commonly used moist form, which is placed in the oral cavity. In 2006, pouch-type tobacco products were marketed in the United States. This type of tobacco is positioned along the gum line, and the user may swallow the juices, making chewing and spitting unnecessary. In the United States, clean indoor air acts and cigarette excise tax increases have resulted in a coincidental increase in smokeless tobacco use.[5] In addition, unlike cigarettes, the majority of smokeless tobacco products are sold without a health warning, and lack of awareness of its negative impact on health increases its consumption.[6]

More recently, e-cigarettes have significantly grown in popularity over the past 5 years, particularly among youth and young adults. According to data from the National Youth Tobacco Surveys (2011-2014), e-cigarettes are now the most commonly used tobacco product among adolescents in the United States.[7] As e-cigarettes are relatively new on the market, there is currently no long-term evidence related to oral and systemic health effects. However, owing to the nicotine level in most e-cigarette products, it is possible that its use may adversely affect oral tissues and immune response, and further studies are needed.[8]

Worldwide, several names are used to denote different smokeless tobacco products. These include plug, gutkha, khiwam, khaini, iq’milk, zarda, naswar, nass, chimo, toombak, shamma, gudhaku, gul, mishri, maras, and moist snus.[9]

The use of smokeless tobacco is associated with a spectrum of oral cavity lesions, including leukoplakia, speckled leukoplakia, erythroplasia, tobacco-associated keratosis, carcinoma in situ (CIS), verrucous carcinoma, and invasive squamous cell carcinoma (SCC). It can cause smokeless tobacco–induced keratosis, gingival inflammation, periodontal inflammation, alveolar bone damage, dental caries, and tooth abrasion. In addition to oral lesions, smokeless tobacco users are at increased risk for stomach and pancreatic cancers, although the data regarding the risks for pancreatic cancer are mixed, with some studies showing a statistical association.[10, 11, 12, 13, 14, 15]

Tobacco-related lesions (smokeless tobacco–related and nicotine stomatitis) comprised 4.7% of all lesions found in 17,235 people examined as part of the Third National Health and Nutrition Examination Survey. Smokeless tobacco users had one of the highest odds of having a lesion present (odds ratio, 3.9).[16]

Gingival inflammation and alveolar bone damage

Studies from the United States report high rates of gingival recession in smokeless tobacco users, and, ultimately, periodontal disease and bone loss. There appears to be an association between the quantity of smokeless tobacco used and the severity of disease. Periodontal pathology is most likely related to long-term use of smokeless tobacco and is more typical in adult populations than in teenagers. However, although gingival and periodontal inflammation and bone damage can clearly be seen in association with smokeless tobacco use, there have not been studies that have been able to eliminate confounding factors such as the use of other forms of tobacco, preexisting periodontal disease, or other systemic diseases such as diabetes that may affect oral hygiene.[17]

Dental caries

Dental caries have been associated with the use of loose-leaf chewing tobacco, and studies have observed that the amount of dental caries has been shown to increase with the amount of chewing tobacco used. Other studies have found a minimal relationship between the two factors, and it has been speculated that the relative lack of dental caries may be secondary to the accelerated salivary flow the tobacco stimulates, which washes away the bacteria that induce the formation of the caries.[17]

Oral leukoplakia

Oral leukoplakia (white plaques) is a common physical finding in 40-50% of people who use smokeless tobacco. Oral leukoplakia is a premalignant lesion, with the risk of malignant transformation to oral cancer varying in relation to the product used. In relation to snuff products, differences in the tobacco species, fermentation processes, nicotine content, tobacco-specific N -nitrosamines content, and pH may account for the differences in the reported risk. With most products, the risk appears quite low, whereas toombak dipping (a regional term for snuff) has been associated with a high incidence of oral cancer in the Sudan.[18, 19] Oral leukoplakia has been shown to regress in as few as 6 weeks with smokeless tobacco cessation.[20]  Note the image below.

Erythroplasia

Erythroplasia (ie, erythroplakia, red plaques) is associated with severe dysplasia or malignancy in 80-90% of cases. Because of the high malignancy rate, the threshold for histologic evaluation of erythroplasia should be low.

Speckled leukoplakia

Speckled leukoplakia is much less common than either leukoplakia or erythroplasia and is distinguished, as the name suggests, by a speckled appearance.

Tobacco-associated keratosis

Tobacco-associated keratosis is a predictable lesion that manifests as an area of thickening at the site of habitual placement of snuff or chewing tobacco. Two distinct grading systems are used to classify lesion stage by degree of clinical thickening. The development of a lesion is dependent on the amount, frequency, type, and brand of smokeless tobacco used.

Carcinoma in situ

Carcinoma in situ may manifest clinically as leukoplakia, erythroplasia, speckled leukoplakia, or tobacco-associated keratosis.

Squamous cell carcinoma

Squamous cell carcinoma (SCC) may arise in areas of oral or speckled leukoplakia, erythroplasia, or verrucous carcinoma. More than 80% of patients with oral SCC smoke, although those who smoke pipes or cigars are at the greatest risk. Overall, SCC accounts for more than 90% of all oral cancers.[21]

Verrucous carcinoma

Verrucous carcinoma (also known as snuff dipper's cancer) is a type of low-grade, slow-growing, exophytic SCC that arises from regions in the mouth where smokeless tobacco is consistently placed. Lesions rarely metastasize but may recur, and, rarely, they transform into invasive SCCs. Although verrucous carcinoma is not the most common oral lesion found in users of smokeless tobacco, most cases of verrucous carcinoma are diagnosed in habitual users of smokeless tobacco. Note the image below.

Oral smokeless tobacco contains numerous carcinogens, including polonium 210, tobacco-specific N -nitrosamines, volatile aldehydes, and polycyclic aromatic hydrocarbons.[22] A 2015 study from the 1999-2012 National Health and Nutrition Examination Survey Data showed that US adults who used only smokeless tobacco products had higher levels of biomarkers of exposure to nicotine and a cancer-causing toxicant—the tobacco-specific nitrosamine NNK—compared with those who used only cigarettes.[23]

In experimental in-vitro systems, smokeless tobacco has shown effects on cell proliferation, apoptosis, and activation of inflammatory mediators. In animal models, evidence of carcinogenesis has been reported for the chewing tobacco and snuff products commercially available for human consumption in Europe and in North America. The mutational spectrum reported a high incidence of H-ras mutations in tobacco chewing oral carcinomas in the Indian population compared with smokers from Western populations.[9]

Approximately twice as much nicotine is absorbed per dose from smokeless tobacco compared with cigarettes (4 mg vs 2 mg); orally absorbed nicotine also stays longer in the bloodstream. The average can of smokeless tobacco has an estimated nicotine content of 144 mg, equal to 80 cigarettes.

Pure nicotine and smokeless tobacco extract have been compared for their oxidative stress actions by measuring the generation of reactive oxygen species. Pure nicotine has been found to be less toxic than smokeless tobacco extract with equivalent amounts of nicotine.[24]

An analysis of the nicotine content of 11 brands of popular smokeless tobacco products found that moist snuff has the highest nicotine content, whereas loose-leaf chewing tobacco has the lowest nicotine content.[25]

In 2006, the International Agency for Research on Cancer (IARC) concluded that smokeless tobacco is carcinogenic in human beings, causing cancer of the oral cavity and pancreas.[26] The IARC noted wide variability between geographic regions in the type and extent of disease caused by use of smokeless tobacco, and that the disease dissimilarities were accompanied by large differences in the concentrations of carcinogens in the tobacco used in different regions. The World Health Organization (WHO) Study Group on Tobacco Product Regulation concluded that the scientific evidence suggests that the differences in carcinogenicity of smokeless tobacco in various regions is due, at least in part, to differences in carcinogen concentrations in the products used.[27]

A 2016 study measuring the effect of smokeless tobacco on fractional exhaled nitric oxide (FeNO)—an noninvasive biomarker of eosinophilic airway inflammation—showed that exposure to smokeless tobacco was associated with lower FeNO compared with no exposure. Since nitric oxide plays an important role in several physiologic processes in the respiratory tract, including counteracting bronchoconstriction and vasoconstriction, inhibiting platelet aggregation, host defense, and cytotoxicity, lower levels may lead to increased vulnerability of the airway to carcinogenic development.[28]

Alcohol consumption, cigarette smoking, candidal infection,[29] and poor dentition are causes of oropharyngeal cancers. Additionally, human papillomavirus (HPV), especially HPV type 16, has been implicated in the pathogenesis of 20-30% of oropharyngeal cancers. People with HPV-related oral cancers seem to have a better prognosis than those without HPV infection, and they are less likely to have a history of tobacco and alcohol use. Finally, exposure to chronic irritants (eg, mouthwash, poorly fitting dentures) may be associated with oral mucosal cancer.

Frequency

United States

Smokeless tobacco products include chewing tobacco, dry snuff, and moist snuff. Consumption of chewing tobacco in the United States decreased from 47 million to 36 million pounds, and dry snuff from 3.5 million pounds to 2.2 million pounds, from 2000-2006. However, during the same period, consumption of moist snuff increased from 61.5 million pounds to 77.4 million pounds.[30]

Smokeless tobacco and its associated lesions affect a large number of persons in the United States, with an estimated 6-22 million people who use smokeless tobacco annually.[31, 32] The popularity of oral forms of snuff and chewing tobacco has rapidly increased in North America, especially among white adolescent males. The National Youth Tobacco Survey of 2004 noted 3.1% of male middle school students and 9.5% of male high school students used smokeless tobacco on at least one of the 30 days preceding the survey.[33]

The percentage of male high school students who used smokeless tobacco on at least 1 of the 30 days preceding a Youth Risk Behavior Survey performed in in 2011 by the US Centers for Disease Control and Prevention (CDC) noted several trends. Nationwide, 7.7% of students had used smokeless tobacco (eg, chewing tobacco, snuff, dip) on at least 1 day during the 30 days before the survey. Overall, the prevalence of current smokeless tobacco use was higher among male (12.8%) than female (2.2%) students and higher in older than in younger high school students. The prevalence of current smokeless tobacco use ranged from 3.5% to 16.9% across state surveys (median, 8.8%). Among students nationwide, the prevalence of current smokeless tobacco use decreased during 1995-2003 (11.4-6.7%) and then did not change significantly during 2003-2011 (6.7-7.7%). The prevalence of current smokeless tobacco use also did not change significantly from 2009 (8.9%) to 2011 (7.7%).[1]

The 2012-2013 National Adult Tobacco Survey indicates the rate of smokeless tobacco use in the United States has remained relatively stagnant, at 3.8% for “every day, some day, or rarely” usage and 2.6% for “every day or some day” usage.[34]

The Adult Tobacco Survey of 2003-2007 of 19 states reported an average of 3.5% of adults used smokeless tobacco, with the highest state surveyed reporting 14.2% use in Oklahoma.[35] In 1999, the Journal of the American Medical Association published state-specific prevalences of cigarette and smokeless tobacco use among adults compiled by the CDC from the 1997 Behavioral Risk Factor Surveillance System.[5] Results of 17 states were published, revealing more than a 6-fold difference in prevalence rates between Arizona and West Virginia (1.4% vs 8.8%, respectively). The states with the highest prevalence rates were West Virginia and Wyoming (the prevalence rates in males were 18.4% and 14.7%, respectively). Smokeless tobacco use among women was less than or equal to 1.7% in all 17 states.

A 2010 study reported an elevated use of smokeless tobacco among the US military personnel, and, in particular, 13.1% of military aviators reported using smokeless tobacco within the past month of the survey, which is much higher than the US national civilian average of 3.5%.[36]

The American Cancer Society’s most recent estimates for oral cavity and oropharyngeal cancers in the United States are for 2016; about 48,330 people will develop oral cavity or oropharyngeal cancer and an estimated 9,570 people will die of these cancers.[37] The death rate for oral cancer is higher than that for malignant melanoma, Hodgkin disease, brain cancer, testicular cancer, or cervical cancer, but it has been decreasing over the past 30 years. Oral cancer is 4 times more likely to occur in users of smokeless tobacco than in those who do not use tobacco products. The annual incidence of oral cancer is estimated at 26 cases per 100,000 users of smokeless tobacco.

International

Worldwide, more than 350,000 new cases of oral and laryngeal cancers are diagnosed each year. According to statistics from the WHO, the incidence of oral cancer shows extensive variation, but is the eleventh most common cancer worldwide.[38] Incidence and mortality rates are higher in men than in women. Differences across countries particularly relate to distinct risk profiles and availability and accessibility of health services.[39]  

A 2015 study evaluating the global burden of disease from smokeless tobacco consumption in adults from 113 countries using a proportion of the disability-adjusted life-years (DALYs) lost and deaths reported found that in 2010, smokeless tobacco use led to 1.7 million DALYs lost and 62,283 deaths due to cancers of mouth, pharynx, and esophagus and 4.7 million DALYs lost and 204,309 deaths from ischemic heart disease, with a significant burden of over 85% from Southeast Asia.[40]

Race

Currently, the incidence of oral cancer is slightly more common in blacks than in whites. The latest statistics from the Surveillance, Epidemiology, and End Results (SEER) database indicate a rate of 17.2 cases per 100,000 black males and 15.7 cases per 100, 000 white males.[41]

Sex

Oral cancer is two times more commonly diagnosed in men than in women.

Age

Smokeless tobacco use usually begins between ages 9 and 16 years. Although the use of smokeless tobacco frequently starts at school age and may continue in middle age, oral cancer is most commonly diagnosed in patients aged 65 years or older. Verrucous carcinoma, specifically, is most commonly diagnosed in men older than 50 years.

The average age of most people diagnosed with cancer of the oral cavity is 62 years, but approximately 30% of these cancers occur in patients younger than 55 years.

The prognosis of smokeless tobacco lesions varies widely depending on the type of lesion, stage of detection, and extent of involvement of the oral cavity and airway. The survival rates are 90-100% for small carcinomas in the hard palate, on the upper part of the gingiva, on the floor of the mouth, and on the buccal mucosa. Moderately advanced lesions without spread to the lymph nodes are associated with a local control rate of as much as 80%, whereas posterior cancers that appear late are associated with a survival rate as low as 30%.

Leukoplakia is benign, while invasive SCC metastasizes via lymphatic spread, usually to the cervical lymph nodes.

Decreased survival rates from smokeless tobacco use are not likely due to oral cancer alone but include many other causes of morbidity and/or mortality. Small studies in specific ethnic populations have shown an increased risk of cardiovascular disease.[42]

Patient handouts regarding smoking cessation techniques and resources (eg, setting a quitting date, group therapy) are available from the National Cancer Institute. Additionally, the National Spit Tobacco Education Program provides patient resources and a list of activities by region.

For patient education resources, see the Cancer and Tumors Center, as well as Cancer of the Mouth and Throat.

Patients may present asymptomatically, admitting only to the use of smokeless tobacco or to the presence of other predisposing risk factors (eg, use of alcohol, exposure to chronic irritants) for premalignant and cancerous lesions. In more advanced disease, patients may report pain, swelling, or dysphagia.

Gingivitis

Gingivitis appears as inflammation and swelling of the gums that may associated with redness and bleeding. Gums may be tender when touched.

Leukoplakia

Leukoplakia refers to a filmy white or yellow patch involving the oral mucosa. The patch may appear translucent or opaque and raised or ulcerated. It may be pumicelike. Leukoplakia is a clinically descriptive term, and other diseases must be ruled out.[43]

Erythroplasia

Erythroplasia appears as a patch with varying degrees of erythema. It most commonly occurs on the floor of the mouth.

Speckled leukoplakia

The lesions are white patches with interspersed areas of erythema. Two thirds of the lesions are located on the buccal mucosa; the tumors are commonly nodular.

Tobacco-associated keratosis

Tobacco-associated keratosis is an ill-defined area of white thickening at the sites where oral smokeless tobacco is habitually placed; most commonly, these areas involve the mandibular labial and buccal mucosal folds. The continued use of smokeless tobacco causes the affected areas to become corrugated and grayer.

Verrucous carcinoma

The lesions appear as exophytic growths with papillary projections, they may be large at the time of diagnosis, and they can cause local tissue destruction. They appear rough surfaced with a broad-base attachment.

Squamous cell carcinoma

The lesions usually have a mixed red and white appearance, with ulceration or inflammation in some cases. The lesions are most commonly found on the floor of the mouth and on the ventral and lateral surfaces of the tongue. Those cancers associated with smokeless tobacco may arise in differing locations associated with quid placement and/or the buccal folds. Swelling or induration is characteristic of invasive growth.

No blood tests are available to help diagnose cancers of the oral cavity.

Typically, imaging studies are reserved for staging purposes once oral cancer has been diagnosed. Chest radiography, barium swallow, MRI, and positron emission tomography scanning may be used to rule out the involvement of other organ systems.

A thorough history, including an assessment of the risk factors, and a careful examination of the oral cavity are the most important clinical tools in diagnosing oral lesions. The physical examination must include an assessment of the cervical lymph nodes. 

In order to better visualize lesions of the throat, base of the tongue, and larynx, indirect pharyngoscopy and laryngoscopy may be performed. In addition, if suspicion for a head or neck cancer is strong, endoscopy may be performed to more thoroughly examine the oral cavity, oropharynx, larynx, esophagus, trachea, and bronchi.

Exfoliative cytology of a suggestive lesion may be performed, but oral cancer can only be definitively diagnosed based on findings from an incisional biopsy.

Tobacco-associated keratosis appears as epidermal thickening or hyperkeratosis and acanthosis. Dysplasia is uncommon in this lesion.

Leukoplakia appears as hyperkeratosis due to chronic irritation in approximately 80% of cases. A minority of lesions shows precancerous changes with varying degrees of dysplasia.

Speckled leukoplakia exhibits both epithelial hyperplasia and epithelial atrophy. Dysplasia occurs in 50-70% of all lesions, but carcinoma is rarely diagnosed. Candidal infection may be a common finding, with an inflammatory infiltrate of lymphocytes and plasma cells in the underlying connective tissue. The role of candidal species in causation of the lesion is unclear.

Erythroplasia shows mild-to-moderate epithelial dysplasia in only 9% of lesions obtained from biopsy samples. Severe dysplasia, carcinoma in situ (CIS), or squamous cell carcinoma (SCC) is often apparent. The clinical size of the lesion is not correlated with microscopic severity.

CIS refers to severe dysplasia extending the full thickness of the epithelium. Grossly, CIS may appear as leukoplakia, speckled leukoplakia, erythroplasia, or keratosis.

At histologic examination, SCC shows increased cellular proliferation, atypical mitotic figures, loss of cell cohesion, and/or atypical keratinization. Invasive growth is indicated by the invasion of tumor cells into the epithelial basement membrane. Verrucous carcinoma is a specific form of SCC that exhibits a high level of differentiation.

See the American Cancer Society detailed guide on oral cavity and oropharyngeal cancer: "How Are Oral Cavity and Oropharyngeal Cancers Staged."

To reduce the risk of progression to oral cancer, smokeless tobacco use should be minimized, with cessation encouraged. The National Cancer Institute recommends that clinicians use the "4 A s," as follows:

• Ask about tobacco use

• Advise patients to quit smoking

• Assist patients in quitting

• Arrange follow-up

A 2010 study comparing the effectiveness of a 4-mg nicotine lozenge with behavior intervention compared with behavioral intervention alone reported no difference between groups for increasing tobacco abstinence, quit attempts, and duration of abstinence.[44]

The National Spit Tobacco Education Program (NSTEP)[45] is a national organization committed to minimizing the risk of oral cancers associated with smokeless tobacco through education. This organization does not advocate smokeless tobacco use as a healthier alternative to cigarette smoking. NSTEP targets education to the general public and specifically to baseball players and their families, in whom the use of smokeless tobacco is extremely high. In fact, NSTEP is supported and endorsed by both Major League Baseball and Little League Baseball.

In 2015, San Francisco became the first US city to ban the use of smokeless tobacco at sporting events, including AT&T Park, home of the city's Major League Baseball team, the Giants. Following step, four additional cities—New York, Boston, Los Angeles, and Chicago—are enacting similar measures.[46]

According to the most recent Cochrane review on interventions for smokeless tobacco use cessation, nicotine replacement therapy and bupropion have not been shown to affect long-term abstinence. Behavioral interventions should be used to help smokeless tobacco users to quit, and telephone counselling or an oral examination may increase abstinence rates.[47]

Biopsy should be performed on lesions of erythroplasia that are suggestive of cancer based on their appearance or location in the oral cavity or those that have failed to resolve within 2-3 weeks. Premalignant lesions and carcinoma in situ (CIS) may be permanently cured after excision or biopsy. Primary and invasive squamous cell carcinomas (SCCs) are treated with varying combinations of surgery and/or radiation.

Once a diagnosis of oral cancer is established, the therapeutic approach is multidisciplinary.

Treatment for oral cancer may involve consultation with the following:

• Dentist
• Head and neck surgeon (otolaryngologist)
• Maxillofacial surgeon
• Radiation oncologist
• Speech therapist
• Surgical oncologist

Several studies have found that a diet low in fruits and vegetables is linked with an increased risk of cancers of the oral cavity and oropharynx.[48]

Cigarette, cigar, or pipe use at each time interval correlated with significantly increased caloric intake in males but not in females. In both males and females, tobacco users consumed more fat, cholesterol, and alcohol.

The National Spit Tobacco Education Program (NSTEP), with funding from the Robert Wood Johnson Foundation and other national organizations, advocates the prevention of smokeless tobacco use through education. Additionally, clinicians should use the "4 A s" proposed by the National Cancer Institute as outlined in Medical Care.

Persons who use smokeless tobacco should have regular follow-up visits to their physician and dentist for oral examinations. Long-term monitoring for the development of new oral lesions is important for early detection and prevention of oral cancer.

The US Public Health Service recommends nicotine replacement therapy (NRT) (nicotine patch, gum, lozenge, inhaler, or nasal spray), bupropion sustained release (SR), and varenicline as first-line treatments for tobacco dependence.[49] There may also be an additive effect when used in combination.

Other medications useful in treating nicotine dependence include nicotine nasal spray inhalers; nicotine gum; nicotine lozenges; and nontobacco snuff products containing mint, clover, alfalfa, and flavorings.[50]  

A 2012 meta-analysis on pharmacologic interventions for treatment of smokeless tobacco use concluded that bupropion and NRT have not demonstrated efficacy for increasing long-term tobacco abstinence rates among smokeless tobacco users. However, bupropion could be used to attenuate postcessation weight gain among smokeless tobacco users trying to become tobacco abstinent, and NRT could be used to increase short-term abstinence rates and to alleviate symptoms of withdrawal. As in cigarette smokers, varenicline seems to be the most effective treatment for smokeless tobacco users attempting to achieve tobacco abstinence. Further research is needed to evaluate high-dose NRT and combination therapy for smokeless tobacco users.[51]

Counseling and medication are effective when used by themselves for treating tobacco dependence. The combination of counseling and medication, however, is more effective than either alone. Thus, clinicians should encourage all individuals making a quit attempt to use both counseling and medication.[49]

Class Summary

These agents are used to aid in smoking cessation, while the patient participates in a behavioral modification program under medical supervision.

Nicotine transdermal system (Nicotrol)

A nicotine transdermal system works best when used in conjunction with a support program, such as counseling, group therapy, or behavioral therapy.

Nicotine polacrilex nasal spray (Nicotrol NS)

Intranasal nicotine may closely approximate the time course of plasma nicotine levels observed after cigarette smoking.

Nicotine transdermal system 21-mg patch (NicoDerm CQ, Habitrol)

The nicotine transdermal system 21-mg patch works best when used in conjunction with a support program, such as counseling, group therapy, or behavioral therapy.

Nicotine polacrilex (Nicorette)

The nicotine is absorbed through the oral mucosa. It is quickly absorbed and closely approximates the time-course of plasma nicotine levels after cigarette smoking.

Bupropion (Zyban, Wellbutrin)

Bupropion is used in conjunction with a support group and/or behavioral counseling. It inhibits neuronal dopamine reuptake. It is also a weak blocker of serotonin and norepinephrine reuptake.

Varenicline (Chantix)

Varenicline is a partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors. Action is thought to result from activity at a nicotinic receptor subtype, where its binding produces agonist activity while simultaneously preventing nicotine binding. The agonistic activity is significantly lower than nicotine. It also elicits moderate affinity for 5-HT3 receptors. Maximum plasma concentrations occur within 3-4 hours after oral administration. Following regular dosing, a steady state is reached within 4 days.